Genome-wide DNA hypomethylation and concomitant site-specific gene hypermethylation are among the most common molecular alterations in human neoplasia. Previous studies revealed that genetic reduction of the DNA methylation level results in opposing effects on tumor development, depending on the tumor cell type and on the different stages of the tumorigenesis. For instance, reduced levels of DNA methylation in mice strongly inhibited tumor development of the intestine, whereas they induced thymic lymphomas and liver tumors. In the present study, using DNA methyltrasferase 1 (Dnmt1) hypomorphic alleles to reduce genomic methylation, we examined the effects of DNA hypomethylation on a murine squamous carcinogenesis in the tongue and esophagus induced by 4-nitroquinoline 1-oxide. Genetic reduction of DNA methylation level led to the suppression of tumor formation in both tongue and esophagus. Histological analyses revealed that DNA hypomethylation preferentially inhibited the development of squamous cell carcinomas. The results suggest that genomic hypomethylation inhibits squamous carcinogenesis in the tongue and esophagus, and that pharmacological modification of epigenetic status might be useful for the prevention and treatment of cancers in the upper digestive tract.